Pathogenesis of Opisthorchiasis induced persistent periductal fibrosis and CCA

在慢性胆胸病中，发病机制表现为一系列明确的阶段，因为胆管吸虫的机械、毒性和免疫机制导致胆道上皮反复损伤，导致慢性炎症反应，从而逐渐重塑胆道上皮的正常组织结构。当个体感染o.v verrini多年（通常是终生），肝内胆管发生持续的组织损伤和修复循环，形成慢性炎症环境，刺激管周纤维生成，并为胆道上皮细胞恶性转化为胆管癌（CCA）提供“阴燃和极化”炎症基础。在项目1中，我们假设存在一种促炎表型，其特征是炎症细胞因子失调，因此，即使在PZQ去除病原体后，具有促炎表型的个体继续产生高水平的IL-6和不可逆的（即持续的）晚期导管周围纤维化（APF）。我们进一步假设这种持续的APF为恶性转化为CCA提供了基础。TMRC项目1将通过以下具体目标，专注于这种慢性炎症表型的过程，以及从感染到持续性APF并最终到恶性转化（CCA）的进展：(1)在泰国Khon Kaen的Chi River流域，继续开展一项基于社区的队列研究，研究与晚期管周纤维化相关的危险因素，将感染者分为“已解决”和“持续”的晚期管周纤维化；(2)确定宿主炎症细胞因子信号通路，如IL-6信号通路，在慢性O. viverrini感染期间诱导进展的风险，无论是解决或持续的晚期管周纤维化和胆管癌；(3)通过微卫星DNA分析来研究弧菌寄生虫的遗传多样性及其与晚期管周纤维化的分离和持续形式的关系。

During chronic opisthorchiasis, pathogenesis is manifested in a series of well-defined stages as the normal tissue architecture of the biliary epithelium is progressively remodeled by the chronic inflammatory response from repeated injury sustained by the biliary epithelium from a combination ofthe mechanical, toxic, and immune mechanisms of the fluke in the bile duct. As individuals are infected with O. viverrini for many years (often a lifetime), a persistent cycle of tissue damage and repair takes place in the intrahepatic biliary ducts, creating a chronic inflammatory milieu that stimulates periductal fibrogenesis and provides the "smoldering and polarized" inflammatory basis for malignant transformation of biliary epithelial cells to cholangiocarcinoma (CCA). In project 1, we hypothesize the existence of a pro-inflammatory phenotype which is characterized by a inflammatory cytokine dysregulation such that, even after removal ofthe pathogen by PZQ, individuals with the pro-inflammatory phenotype continue to produce high levels of IL-6 and an unreversed (i.e., persistent) form of Advanced Periductal Fibrosis (APF). We further hypothesize that this persistent APF provides the basis for malignant transformation to CCA. Project 1 ofthe TMRC will focus on the processes involved in this chronic inflammatory phenotype and the progression from infection to persistent APF and eventually to malignant transformation (CCA) by undertaking the following specific aims: (1) continuing our a community-based cohort study for the risk factors associated with Advanced Periductal Fibrosis in villages with high O. viverrini transmission along the Chi River basin in Khon Kaen, Thailand to stratify infected individuals into those with "resolved" and "persistent" Advanced Periductal Fibrosis; (2) to determine the host inflammatory cytokine signaling pathways, such as the IL-6 signaling pathways, induced during chronic O. viverrini infection on the risk of progressing either resolved or persistent advanced periductal fibrosis, and bile duct cancer; and (3) examine the genetic diversity ofthe O. viverrini parasite by microsatellite DNA analysis and its association with resolved and persistent forms advanced periductal fibrosis. .